US5697922A - Delivery device having encapsulated excipients - Google Patents

Delivery device having encapsulated excipients Download PDF

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US5697922A
US5697922A US08/424,476 US42447695A US5697922A US 5697922 A US5697922 A US 5697922A US 42447695 A US42447695 A US 42447695A US 5697922 A US5697922 A US 5697922A
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beneficial agent
solubility
macroparticulate
release
coating
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Avinash G. Thombre
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Pfizer Inc
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Pfizer Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material

Definitions

  • This invention relates to devices useful for the delivery of a beneficial agent to an environment of use.
  • osmagents cause an osmotic pressure gradient across the device wall and imbibe fluid into the device.
  • Such delivery devices release their active agents either by osmotic pumping or by diffusion or by a combination of the two mechanisms. Since the active agent is released from the device as an aqueous solution, the release rate is dependent on the solubility of the active agent in water. This release rate dependence on the solubility of the active agent can inhibit the attainment of a preferred release rate profile.
  • a solubility enhancing agent may be added to the device core.
  • an excipient which decreases the active agent solubility may be added to the device core.
  • U.S. Pat. No. 4,755,180 ('180) describes such solubility modifying excipients and discloses coating of the excipients with a polymer coating in order to control the release of the excipient.
  • the '180 patent discloses "osmagents" (beneficial agent solubility modifying agents) having various forms such as particles, powders and the like.
  • the release rate controlling film has a thickness of 1 to 20 mils, and in a preferred embodiment, has a thickness of 2 to 10 mils.
  • This pump-in-a-pump design prevented the rapid depletion, and large attendant concentration variation, of the solubility modulating agent (sodium chloride) within the diltiazem hydrochloride core tablet environment.
  • the release of the solubility modulator was controllable and, was designed to provide modulation of the drug solubility for a prolonged period.
  • an asymmetric membrane to coat the device core.
  • That publication discloses an asymmetric membrane having two regions or membrane layers.
  • the substructure is relatively thick and very porous in nature. This substructure supports the other portion of the membrane, a dense, thin skin.
  • This invention is directed to an asymmetric membrane delivery device having coated, macroparticulate, beneficial agent- solubility modifiers for use in dispensing a beneficial agent to an aqueous environment of use.
  • the device comprises a beneficial agent, an osmagent, a macroparticulate solubility modifier and an asymmetric membrane that surrounds the device components.
  • the solubility modifier is coated.
  • the solubility modifier or beneficial agent may be the osmagent or there may be a separate osmagent.
  • Another aspect of this invention is a method for the delivery of a beneficial agent to an environment of use which comprises placing the above device into the environment of use.
  • FIG. 1 discloses a schematic cross-sectional view of an exemplary device of the invention.
  • FIG. 2 is a graph of beneficial agent released from an asymmetric membrane coated capsule having uncoated excipients.
  • FIG. 3 is a graph of beneficial agent release from an asymmetric membrane coated capsule having coated excipients.
  • FIG. 4 is a graph of beneficial agent release from an asymmetric membrane coated capsule having uncoated excipients illustrating different release profiles.
  • FIG. 5 is a graph of beneficial agent release from an asymmetric membrane coated capsule having a combination of coated and uncoated excipients.
  • FIG. 6 is a graph of beneficial agent release from an asymmetric membrane coated capsule having coated excipients with different time lags.
  • Any material may be used to modify the solubility of the beneficial agent that is appropriate for the proposed delivery device use.
  • This material may also function as the osmagent or a separate osmagent may be used.
  • the solubility change can be due to pH, i.e., when the excipient is an acid or alkaline agent or a buffer, or it can be due to a common-ion effect, or by any other mechanism.
  • the solubility modifier increases the solubility (in the aqueous environment) of a beneficial agent exhibiting low solubility (i.e., less than about 5 mg/ml) or decreases the solubility (in the aqueous environment) of a beneficial agent exhibiting high solubility (i.e., greater than about 300 mg/ml). It is especially preferred that a solubility modifier is used that provides a predetermined beneficial agent solubility and consequently a predetermined beneficial agent release profile (i.e. controlled release).
  • any osmagent may be used that is appropriate for the desired application.
  • the solubility modifier may also act as the osmagent or there may be a separate osmagent.
  • the beneficial agent (described below) may also act as the osmagent, by itself, or in combination with the solubility modifier.
  • the solubility modifier may alter the solubility of the beneficial agent causing it to act as the osmagent. It is intended that the above embodiments are within the scope of the invention.
  • the osmagent is a substance which, in solution, exhibits a certain osmotic pressure that is the driving force for water ingress into the device (this increases the internal hydrostatic pressure resulting in release of a substance through a barrier membrane).
  • the osmagent increases the osmotic pressure to above about seven atmospheres which is the normal pressure in mammalian body fluids.
  • one component may function as both the osmagent and the solubility modifier or there can be a combination of components.
  • certain substances such as magnesium carbonate hydroxide, affect the pH, and, thus the solubility of the beneficial agent but are not substantially soluble themselves in the aqueous solution, and thus, do not appreciably affect the osmotic pressure.
  • Exemplary osmotic agent/solubility modifiers include: sugars such as sucrose, lactose, mannitol, maltose, sorbitol and fructose; neutral salts such as sodium chloride, magnesium sulfate, magnesium chloride, potassium sulfate, sodium carbonate, sodium sulfite, potassium acid phosphate, sodium acetate and ethyl acetate; acidic components such as fumaric acid, maleic acid, adipic acid, citric acid and ascorbic acid; alkaline components such as tris(hydroxylmethyl) aminomethane (TRIS); meglumine, tribasic and dibasic phosphates of sodium and potassium; amino acids such as glycine and arginine; and other compounds such as urea.
  • sugars such as sucrose, lactose, mannitol, maltose, sorbitol and fructose
  • neutral salts such as sodium chloride, magnesium sulfate
  • colligative properties of these substances such as osmotic pressures, and other physicochemical properties such as solubility, pKa, etc. are given in several handbooks and reference books (e.g., Handbook of Chemistry and Physics, The Merck Index, etc.).
  • Preferred osmagent/solubility modifiers include acidic and alkaline agents such as fumaric acid, citric acid, TRIS and meglumine.
  • macroparticulates By macroparticulates is meant the coated excipients are 0.16 cm to 1.27 cm in diameter. It is especially preferred that the coated excipients are about 0.48 cm to 0.64 cm in diameter. These sizes differentiate the coated excipients from the fine powders or crystals that have been used previously as described in the Background Art. It is also preferred that the macroparticulates comprise from about 10% to about 90% by weight of the core of the device. Preferably two to four macroparticulates are used. These sizes provide various advantages such as facilitating the choice of a wide variety of polymer coatings. For example, only a few types of coatings can be used to provide prolonged (e.g. twelve hour duration) release coating from very small core particles because the coatings would have to possess a very low permeability.
  • a very thick coating is used to achieve the low permeability, it is possible that some of the excipient in the solubility modifier core would be adsorbed to the coating and not released.
  • a larger macroparticulate can use a thinner coating relative to a smaller particulate to achieve prolonged release, with a less probability that the excipient is trapped in the heavy coating.
  • Another advantage of the macroparticulates is that they are significantly easier to coat than the smaller granules used by the prior art.
  • macroparticulates allows the use of a lower coating weight, thereby conserving materials, allowing the coating operation to be finished in a reasonable period of time (i.e., manufacturability), and providing more flexibility with respect to the dose and amount of excipients that can be incorporated into a reasonable sized device.
  • Another advantage resulting from the macroparticulates is that the solid undissolved solubility modifier persists for a longer period of time in the macroparticulate core which provides a constant gradient for water intake or water ingress into the core of the macroparticulate as well as drug release for a longer period of time. Thus, this results in more effective utilization of the excipient.
  • any coating e.g. film, membrane
  • the coating provides a predetermined release profile for the solubility modifier.
  • the excipient coating provides a release profile having a predetermined time lag.
  • Particularly preferred time lags are from 1 to 10 hours. This is particularly beneficial for those devices where the formulation, by itself, would have released incompletely, but with the solubility modifier present during the final release period, completely releases the beneficial agent is achieved. This is also beneficial when a time lag before drug release is desired. For example, a time lag before the onset of drug release may be beneficial because it would protect a drug which was susceptible to degradation in the acidic environment of the stomach.
  • Such a device would also be useful in providing repeat-action or pulsatile delivery, i.e., periods of no drug release in between periods of drug release at a predetermined rate and over a predetermined duration.
  • Two or more solubility modifier coated macroparticulates having different time lags may be combined to achieve the desired beneficial agent release profile. This, of course, could include the use of two different solubility modifier compounds coated to give the desired time lags.
  • Time lag release coatings are known in the art and may be achieved by a number of mechanisms. For example the time lag may be caused by the use of traditional enteric coatings or slowly dissolving polymers.
  • Time lag release coatings may also be achieved by the use of other mechanisms such as osmotic bursting and chemical degradation of the coating (e.g., hydrolysis).
  • Time lag release coatings may be achieved by varying the coating thickness, coating composition, surface area and size, coating permeability and/or weight proportion of macroparticulate to the device core. For example, by increasing the ratio of polymer to hydrophilic plasticizer (pore former), the time lag is increased (e.g., the higher the proportion of cellulose acetate to polyethylene glycol the longer the time lag will be).
  • the excipient coating provides a release profile that yields a predetermined excipient release duration.
  • Particularly preferred excipient release durations are from 4 to 24 hours. This is particularly beneficial for those devices where the formulation, by itself, would have released incompletely but with the solubility modifier present during the final release period, completely releases the beneficial agent. This duration modification may be achieved in analogous manners to that used to achieve the time lag.
  • the excipient coating provides a release profile that yields a predetermined excipient release rate profile (e.g. constant, increasing, decreasing). This, in turn, would provide the corresponding predetermined release rate profile for the active agent (e.g., constant, increasing, or decreasing). In most cases, a constant release rate profile of the beneficial agent is desired to maximize the duration of therapeutic concentrations. However, in some cases, for example, in order to take advantage of chronopharmacokinetics or, depending on the natural progression of the disease for which treatment is sought or, in devices that have a biofeedback loop incorporated in them, decreasing or increasing release profiles may be preferred.
  • coated excipients such as those described above and uncoated excipients be used as this enables the further tailoring of the beneficial agent release profile.
  • the uncoated excipient will be available to perform its function at early times without any time-lag while the excipient that is coated will be available at later times, or over a prolonged period of time.
  • a predetermined release profile for the solubility modifier can also be achieved by means other than coated macroparticulates.
  • the solubility modifer can be formulated as a matrix tablet with hydrophilic polymers (e.g., hydroxypropylcellulose, hydroxypropylmethyl cellulose, etc.) which operates by a diffusion-dissolution and/or an erosion mechanism.
  • hydrophilic polymers e.g., hydroxypropylcellulose, hydroxypropylmethyl cellulose, etc.
  • Other release mechanisms such as diffusion through barriers in series, osmotic bursting, etc., can also be utilized to affect the release profile of the solubility modifier.
  • Polymers which have a pH dependent solubility e.g., cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate etc.,
  • those (e.g., poly(ortho esters), polyanhydrides etc.) that degrade chemically (e.g., by hydrolysis and oxidation) can also be used to achieve a predetermined release profile for the solubility modifier by means that are well known in the art of controlled release.
  • the rate of release of solubility modifier may be determined by techniques known in the art such as are described in U.S. Pat. No. 4,755,180.
  • the macroparticulate coating is made from a film-forming polymer with appropriate permeability characteristics (e.g., water-insoluble film-forming polymers such as cellulose derivatives).
  • a film-forming polymer with appropriate permeability characteristics e.g., water-insoluble film-forming polymers such as cellulose derivatives.
  • the molecular weight or molecular weight distribution of the polymers is such that coatings made from these polymers have adequate mechanical properties for the desired application.
  • Typical polymer types include olefin and vinyl-type polymers, condensation-type polymers, addition type polymers, organo-silicon polymers, etc.
  • Particularly preferred polymers include polyacrylics, polyethylenes, polysulfones, polyamides, polyurethanes, polypropylene, ethylene-vinyl acetate, polyvinyl chloride, polyvinyl alcohol, ethylenevinyl alcohol, polyvinylidene fluoride, glycols, polyethylene glycol and polymethyl methacrylate. Copolymers of the above polymers such as copolymers of acrylic and methacrylic acid (Eudragit polymer line, Rohm Pharma, Germany) may also be used.
  • the polymers can also include fats, waxes and silicone elastomers. It is especially preferred that the cellulose esters and cellulose ethers are used.
  • Examples include cellulose acetates (acetyl content varying from 31% to 43.9% corresponding to a degree of substitution from 2.1 to 2.9) and cellulose acetate butyrates (butyl content from 17% to 50%) and blends of cellulose acetates and cellulose acetate butyrates. These are generally commercially available from Eastman Chemicals, Kingsport, Tenn., FMC Corporation, Philadelphia, Pa., and Dow Chemicals, Midland, Mich. In addition, cellulose ethers such as ethylcellulose and blends of cellulose ethers and cellulose esters such as methylcellulose, ethylcellulose-cellulose acetate and ethylcellulose-acetate butyrate are preferred.
  • soluble polymers such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone can also be used.
  • HPMC hydroxypropyl methylcellulose
  • HPC hydroxypropyl cellulose
  • HPC hydroxypropyl cellulose
  • HPC hydroxypropyl cellulose
  • HPC hydroxypropyl cellulose
  • HPC hydroxypropyl cellulose
  • HPC hydroxypropyl cellulose
  • HPC hydroxyethyl cellulose
  • sodium carboxymethylcellulose sodium carboxymethylcellulose
  • polyvinylpyrrolidone polyvinylpyrrolidone
  • the macroparticulate coating can also contain other materials such as plasticizers, pore-formers, dyes, etc.
  • Plasticizers reduce the brittleness of polymer films, and increase their flexibility and mechanical strength, and alter their permeability.
  • Plasticizers can be chosen from the following hydrophilic and hydrophobic materials: glycerine, polyethylene glycols (available as Carbowax from Union Carbide, Danbury, Conn.
  • polypropylene glycols polypropylene glycols, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, glyceryl stearate, triethylcitrate, tributylcitrate, dibutyl sebacate, diethyl phthalate, acetyl tributyl acetate, triacetin acetylated monoglycerides, castor oil and soybean oil.
  • the solubility modifier coating can have any structure or be made of any material that controls the release profile of the solubility modifier, it is preferred that the coating be a polymeric coating that becomes permeable to the excipient upon exposure to the aqueous environment.
  • the water soluble component that is added to the film forming polymer may be out leaving a porous membrane.
  • the macroparticulate coating can be asymmetric (as described below) or dense. Generally, depending on the process used to make the coating, it can have a layered (stratified) structure as in layers of asymmetric membrane or layers of dense membranes.
  • the coating can also be semipermeable, i.e., permeable to water but not the solubility modifier.
  • the coating can also have one or more holes (between 100 ⁇ m and 2 mm) or many macro (1 to 100 microns) and micro (less than 1 micron) pores. Coatings having a combination of micro- and macro-pores can also function by osmotic pumping since water ingress into the device can be via the micro-pores and through the polymer while the excipient is pumped out from the macro-pores. Further, the coating can consist of a network of interconnected water-filled pores through which the excipient is released by diffusion. In general, the greater the number of larger pores, the more the contribution by diffusive delivery versus osmotic delivery. The pores can be formed as part of the manufacturing process.
  • pores can also be formed after exposure of the coated excipient to water due to leaching of a phase-separated water soluble component (solid or liquid) in the excipient coating or by sublimation of a component from the film, typically during the drying operation.
  • the pores can also be formed by "osmotic bursting" by incorporation of a swellable component (e.g. hydrogel) in the device or through bursting of a weak portion of the coating.
  • the weak portion can be intentionally built-in into the coating as part of the manufacturing process.
  • the macroparticulate core weight is coating.
  • the macroparticulate coating is about 1 ⁇ m to 1 mm in thickness.
  • the macroparticulate coating is about 10 ⁇ m to 300 ⁇ m in thickness,
  • the pore size is 1 ⁇ m to 100 ⁇ m in diameter and the porosity void volume may vary from 20% to 95%.
  • the hole size is preferably between 100 microns and 1.5 mm.
  • the asymmetric membrane that surrounds the device core components may be any asymmetric membrane that provides the desired release profile for the particular application chosen.
  • Asymmetric membranes are described in "The Use of Asymmetric Membranes in Delivery Devices" E.P.O. Pub. No. 0357369 the U.S. equivalent of which is U.S. application Ser. No. 391,741, the disclosure of which is hereby incorporated by reference.
  • an asymmetric membrane is comprised of two regions of membrane layers. The substructure is relatively thick and very porous in nature. This substructure supports the other portion of the membrane, a very dense, thin skin. Generally, the asymmetric membrane dense skin is 3 ⁇ m to 6 ⁇ m and the substructure is 4 ⁇ m to 300 ⁇ m.
  • the overall thickness is from 10 ⁇ m to 300 ⁇ m. Typically this corresponds to 5% to 30% by weight based on the core weight.
  • Typical polymers used in fabricating asymmetric membranes are cellulose derivatives, polysulfones, polyamides, polyurethanes, polypropylene ethylene-vinyl acetate polyvinylchloride, polyvinyl alcohol, ethylene vinyl alcohol, polyvinylidene fluoride and polymethyl methacrylate.
  • the beneficial agents used in the devices of this invention include, for example, any physiologically or pharmacologically active substance that produces a ocalized or systemic effect in animals including mammals (e.g., human beings).
  • mammals e.g., human beings.
  • the beneficial agents, their therapeutic properties and their solubilities are known to the drug dispensing art in Pharmaceutical Sciences, by Remington, 15th. Ed., 1975 published by the Mack Publishing Co., Easton, Pa.; and in USAN and the USP Dictionary of Drug Names, Mary G. Griffiths Ed., 1985, published by USP Convention Inc., Rockville, Md.
  • active agents include inorganic and organic compounds such as drugs that act on the peripheral nerves, adrenergic receptors, cholinergic receptors, nervous system, skeletal muscles, cardiovascular smooth muscles, blood circulatory system, synaptic sites, neuroeffector junctional sites, endocrine and hormone systems, immunological system, reproductive system, autoacoid systems, alimentary and excretory systems, inhibitors of autocoids and histamine systems.
  • drugs that act on the peripheral nerves, adrenergic receptors, cholinergic receptors, nervous system, skeletal muscles, cardiovascular smooth muscles, blood circulatory system, synaptic sites, neuroeffector junctional sites, endocrine and hormone systems, immunological system, reproductive system, autoacoid systems, alimentary and excretory systems, inhibitors of autocoids and histamine systems.
  • the pharmaceutical agent that can be delivered for acting on these systems includes antidepressants, hypnotics, sedatives, psychic energizers, tranquilizers, anti-convulsants, muscle relaxants, antisecretories, anti-parkinson agents, analgesics, anti-inflammatory agents, local anesthetics, muscle contractants, antibiotics, anti-microbials, anthelmintics, anti-malarials, hormonal agents, contraceptives, histamines, antihistamines, adrenergic agents, diuretics, antiscabiosis, anti-pediculars, anti-parasitics, anti-neoplastic agents, hypoglycemics, electrolytes, vitamins, diagnostic agents and cardiovascular pharmaceuticals.
  • prodrugs of the above-described drugs are also included in such active substances.
  • Such drugs or prodrugs can be in a variety of forms such as the pharmaceutically acceptable salts thereof.
  • beneficial agent is also meant to include other substances for which it is desirable and/or advantageous to control delivery into an environment of use.
  • examples of such substances include fertilizers, algacides, reaction catalysts and enzymes.
  • viscosity modifiers examples include viscosity modifiers, antioxidants, stabilizers, flavoring agents, binding agents, tablet disintegrants, lubricants, gildants, adsorbents, inert diluents, surfactants etc.
  • binding agents such as carboxymethyl cellulose, hydroxyethyl cellulose, acacia gum, guar gum, microcrystalline cellulose, starch sodium polyethylene glycols, corn syrup, sucrose, lactose, mannitol, calcium phosphate and ethyl cellulose; tablet disintegrants such as starch, microcrystalline cellulose, clays and sodium alginate; lubricants such as talc, polyethylene glycol, corn starch, sodium benzoate and sodium acetate; gildants such as microfine silicas, corn starch, microcrystalline cellulose and talc; adsorbents such as silicas and starches; and inert diluents such as lactose, dextrose, starch, microcrystalline cellulose, calcium phosphate, calcium sulfate, sucrose, mannitol, kaolin and magnesium aluminum sulfate.
  • binding agents such as carboxymethyl cellulose, hydroxyethyl cellulose, acacia
  • the devices of this invention can also be administered within a capsule comprising a water soluble wall.
  • the devices can be manufactured to be of suitable size for inclusion either singularly or multiply within a gelatin capsule such that when the capsule dissolves the device(s) are released into the environment of use.
  • the devices to be included within a capsule can be of a variety of shapes, a preferred shape for such devices is spherical or substantially spherical.
  • the exact number and size of such devices can and will be determined according to a variety of well know factors.
  • the environment of use, the beneficial agent or agents, the amount of beneficial agent and the rate of release are all factors to be considered in determining the size, shape, and number of devices to be included in such capsules as well as the composition of the capsule.
  • the dispensing device shape and dimensions can vary based on the particular application (e.g., tablet). Common exemplary shapes are spherical cylindrical, tablet-shaped and capsular-shaped.
  • the dispensing device dimensions may vary with the desired application (e.g., cattle tablets, human tablets).
  • the shape and size may also vary depending on the application so that, for example, the tablet is suitable depending on the quantity and rate of beneficial agent delivery which vary based on the application.
  • the tablet is 0.16 cm to 1.27 cm in size and the beads are 0.2 mm to 2.5 mm in size.
  • Typical capsule dimensions range from about 1 cm to about 2.54 cm in length and about 0.25 cm to about 1.1 cm in diameter for human health applications. For animal applications such as ruminal delivery to cattle, typical dimensions range from about 5.1 cm to about 10.2 cm in length and about 1.3 cm to about 3.1 cm inches in diameter.
  • the beneficial agent comprises up to 50% of the weight of the device
  • the solubility modifier macroparticulate comprises up to 90% of the weight of the device
  • the osmagent comprises up to 90% of the weight of the device
  • the other excipients comprise up to 50% of the weight of the device.
  • the macroparticulate coating comprises 5% to 45% of the weight of the beneficial agent and solubility modifier macroparticulate.
  • the asymmetric membrane comprises 5% to 30% of the weight of all the device components.
  • FIG. 1 the beneficial agent and other excipients 3 are surrounded by asymmetric membrane capsule halves 6. External to the device 1 is the environment of use 15 including the aqueous solution. Inside the capsule halves 6 is one compressed macroparticulate 9 having a coating 12 thereon and another compressed macroparticulate 18 which is uncoated.
  • Preferred devices include those with an asymmetric membrane coating comprising cellulose acetate/glycerine and optionally triethyl citrate surrounding the beneficial agent, cellulose acetate/polyethylene glycol coated macroparticulates and other excipients.
  • the macroparticulates comprise meglumine (N-methyl glucamine).
  • the weight proportion of cellulose acetate to polyethylene glycol is about 1/1 to 10/1 and that the weight proportion of the coating to the macroparticulate core is about 5% to about 30%. It is especially preferred that there are 1 to 4 macroparticulates having a size of about 0.48 cm to 0.64 cm.
  • coated macroparticulate particles of this invention are made by standard procedures such as wet or dry granulation of the desired formulation followed by compression into a tablet.
  • compressed tablets of the desired formulation can be made by direct compression, i.e., without a granulation step prior to compression.
  • Macroparticulates in the form of beads, spheres, or rounded shapes
  • Macroparticulates may also be prepared by an extrusion-spheronization process in which the desired blend is wet-massed, extruded in an extruder (e.g., Luwa EXKS-1 extruder, LCI, Charlotte, N.C. or the Calera Model 40 extruder G.B.
  • spheronizer e.g., Luwa QJ-230 marumerizer, LCI, Charlotte, N.C. or the Calera Model 15 spheronizer, G.B. Caleva Ltd., Dorset, England
  • tray drying in a forced-air convection oven, fluid bed dryer, or vacuum dryer.
  • Other drying methods such as microwave drying can also be used.
  • the macroparticulates are then optionally film-coated according to standard procedures with the desired coating by repeatedly dipping them into a coating solution and drying in-between dippings or, on a larger scale, by using conventional or side-vented coating pans (e.g., the Accela-Cota, Thomas Engineering, Hoffman Estates, Ill., the Vector-Freund Hi-Coater, Marion, Iowa, and the Driacoater, Driam USA, Spartanburg, S.C.).
  • fluid-bed coating equipment with top-spray (granulator), bottom spray (Wurster), and tangential spray (rotor-processor) can also be used to apply the film-coat onto the macroparticulates.
  • Such fluid-bed coating equipment is available from vendors such as Glatt Air Techniques, Ramsey, N.J. and from Aeromatic Inc., Columbia, N.J., and Vector Corporation, Marion, Iowa.
  • the active agent formulation in the present invention can simply be a homogeneous blend of the active agent and other excipients achieved by mixing or it can be a granulation prepared by standard dry or wet granulation techniques.
  • a wet-granulation technique a blend of the dry components is wet-massed with water or with nonaqueous solvents. The wet mass is then dried and milled to achieve the desired particle size distribution.
  • Capsule formulations may be prepared by forming a cap and body of the above-described polymers.
  • polymers may be molded into the desired shapes and sintered followed by dip-coating with an asymmetric membrane.
  • hard gelatin capsules may be coated with the asymmetric membrane.
  • These semipermeable capsule bodies and caps are then filled with the beneficial agent, macroparticulates and other excipients using standard capsule filling techniques. Then, the capsule is sealed and assembled according to standard techniques. This may be performed using conventional capsule-sealing equipment.
  • Tablets may be prepared using conventional processes and conventional tabletting and tablet-coating equipment. The tablet cores can be made by direct compression of the beneficial agent, macroparticulates and other desired excipients or other common tabletting methods.
  • phase-inversion methods may be used to apply an asymmetric coating to the capsules or tablets (e.g., E.P.O. 0357369).
  • phase-inversion methods include the vapor quench process, the dry process, the liquid quench process, and the thermal process.
  • Asymmetric membrane coatings can also be made by interfacial polymerization (e.g., E.P.O. Pub. No. 0357369).
  • membrane formation is accomplished by penetration of a precipitant for the polymer into the solution film from the vapor phase, which may be saturated with the solvent used.
  • a porous membrane is produced without a skin and with an even distribution of pores over the membrane thickness.
  • the polymer In the dry process, the polymer is dissolved in a mixture of a solvent and a poor solvent, of which the former solvent is more volatile.
  • the polymer precipitates when the mixture shifts in composition during evaporation to a higher nonsolvent content.
  • a skinned or nonskinned microporous membrane can be the result.
  • film formation is caused by the immersion of the cast polymer film in a nonsolvent bath.
  • the polymer precipitates as a result of solvent loss and nonsolvent penetration (exchange of the solvent with non-solvent).
  • a skinned or nonskinned membrane can be the result.
  • a solution of polymer in a mixed solvent which is on the verge of precipitation, is brought to phase separation by a cooling step.
  • the membrane can have a skin.
  • Microporous asymmetric coatings can also be made by inclusion of a leachable component in the coating formulation.
  • a leachable component for example, a small molecular weight sugar, salt, or water soluble polymer particles can be suspended or dissolved in the coating solution. Once the coating is applied, then the water-soluble materials can be leached out by immersion in water, forming a microporous asymmetric coating.
  • Asymmetric membrane capsules were made by a phase inversion process in which the membrane was precipitated on a mold pin by dipping the mold pin in a coating solution followed by quenching in an aqueous solution.
  • cylindrical stainless steel mold pins about 5.1 cm long with diameters that allowed the cast halves to snugly fit each other were used, They were first lubricated with a silicone fluid (Dow MDX4 Medical Grade Fluid, Dow Chemicals, Midland, Mich.) diluted in methylene chloride.
  • the silicone fluid served as a release agent, i.e., it aided the stripping of the capsule half after drying.
  • the mold pins were then dipped into a solution consisting of cellulose acetate/acetone/ethyl alcohol/glycerine citrate (15/49/28/8). This was followed by slowly withdrawing the mold pins from the solution and rotating them twice, to evenly distribute the polymer around the pins. As the polymer solution became increasingly viscous because of phase separation, it formed a capsular shape over the mold-pins. Then, the mold-pins were lowered into a 90/10 mixture of water/glycerine to quench. After about 15 minutes in the quench bath, the pins were withdrawn and allowed to dry at room temperature. After drying, the capsule shells were stripped off the pins by a stripping collar, trimmed to size with a razor blade, and the two halves joined. The cycle time from dipping to stripping was about 45 to 55 minutes.
  • the body of the asymmetric membrane capsules was filled with 20 mg glipizide (approximately 12%), mixtures of TRIS (tromethamine, tris(hydroxymethyl)aminomethane, or THAM) and fructose in the proportions given in Table 1, and 0.5% magnesium stearate.
  • FIG. 2 graphs percent % glipizide released (Y) against time in hours (X) for the various formulations keyed to Table 1.
  • Glipizide was completely released from Formulation I containing TRIS as the major component (no fructose) over a 2 to 3 hour period.
  • TRIS as the major component
  • fructose as the major component
  • the initial release rate of glipizide was reduced.
  • the extent of release was progressively lower.
  • the maximal extent of glipizide released decreased with a decrease in the TRIS content of the formulation.
  • Table 2 lists the initial release rate (calculated from the initial slope of the release profile), the maximal extent of glipizide released, and the time to release 90% of the maximal extent.
  • This example demonstrates control of the initial release rate and the maximal extent of glipizide released from asymmetric membrane capsules by selecting the proper fill formulation.
  • Asymmetric membrane capsules were fabricated as described in Example 1 and were filled with a #60-100 mesh granulation consisting of glipizide/lactose/Klucel EF 15/80/5 (Klucel EF Hydroxypropylcellulose, Aqualon, Wilmington, Del.). The granulation was made by a standard aqueous wet granulation process. In addition to this granulation, the capsules were filled with 0.48 cm meglumine (sometimes referred to as N-methyl glucamine) tablets that were, in some cases, film-coated with a cellulose acetate/polyethylene glycol 1000 (M.W.) (CA/PEG) membrane.
  • M.W. cellulose acetate/polyethylene glycol 1000
  • the coated meglumine tablets were made by wet granulating a 95/5 mixture of meglumine/Klucel-EF. A 9/1 mixture of magnesium stearate/sodium lauryl sulfate and colloidal silicon dioxide were added to the meglumine granulation and this blend was compressed into 0.48 cm tablets using the Type F (Manesty, Liverpool, England) tabletting machine. The meglumine tablets were spray film-coated at the 10% w/w core or 20% w/w core level with a 9/1 CA/PEG 1000.
  • FIG. 3 graphs percent % glipizide released (Y) against time in hours (X) for the various formulations keyed to Table 3. After the reproducible time-lag, drug release occurred at a relatively rapid rate that was characteristic of a capsule formulations containing glipizide and meglumine.
  • the time-lag data are summarized in Table 3.
  • time-lag can be controlled before the onset of drug release from asymmetric membrane capsules by filling the capsules with a drug granulation as well as an encapsulated excipient formulation.
  • the magnitude of the time-lag can be controlled by selecting the coating level and the film coat surrounding the excipient tablet.
  • Asymmetric membrane capsules consisting of cellulose acetate/acetone/ethyl alcohol/glycerine/triethylcitrate 15/49/28/3/5 were made by the process described in Example 1. They were then filled with formulations designated I through III shown in Table 4. Formulation I was made by a conventional aqueous wet-granulation method and sized to #60-100 mesh while Formulations II and III were made by blending, screening, and reblending.
  • FIG. 4 graphs percent (%) glipizide released (Y) against time in hours (X) for the formulations keyed to Table 4.
  • the glipizide release rates were calculated as a function of time from the release profiles. These indicate a decreasing, constant, and increasing rate of glipizide release depending on the formulation used.
  • Asymmetric membrane capsules were made as in Example 3 and filled with the following:
  • glipizide granulation containing 9.5% glipizide, 20% TRIS, 70% lactose, and 0.5% magnesium stearate, and
  • meglumine tablet coated with a 9/1 cellulose acetate/polyethylene glycol-1000 (CA/PEG) coat at 10% (w/w core) level.
  • the meglumine tablet itself was made by combining and compressing a meglumine granulation (93%), 9/1 magnesium stearate/sodium lauryl sulfate (5%), and colloidal silicon dioxide (Cabosil) (2%).
  • the meglumine granulation was prepared by a wet-granulation of meglumine (95%) and hydroxypropylcellulose (Klucel) (5%).
  • the glipizide granulation by itself, was expected to give the following release characteristics: initial release rate, 16.3%/hr; maximal extent of glipizide release, 46%; time for releasing 90% of the glipizide in this formulation, 4.5 hours.
  • the actual glipizide release profile obtained with this formulation is shown in FIG. 5.
  • FIG. 5 graphs percent (%) glipizide released (Y) against time in hours.
  • Asymmetric membrane capsules were made as in Example 3 and filled with the following:
  • glipizide granulation containing 15% glipizide, 80% lactose, and 5% hydroxypropylcellulose (Klucel),
  • meglumine tablet coated with a 6/4 cellulose acetate/polyethylene glycol-1000 (CA/PEG) coat at 10% (w/w core) level.
  • the meglumine tablet itself was made by combining and compressing a meglumine granulation (93%), 9/1 magnesium stearate/sodium lauryl sulfate (5%) and colloidal silicon dioxide (Cabosil) (2%).
  • the meglumine granulation was prepared by a wet-granulation of meglumine (95%) and hydroxypropylcellulose (Klucel) (5%), and
  • meglumine tablet coated with a 9/1 cellulose acetate/polyethylene glycol-1000 (CA/PEG) coat at 20% (w/w core) level.
  • the meglumine tablet itself was made by combining and compressing a meglumine granulation (93%), 9/1 magnesium stearate/sodium lauryl sulfate (5%) and colloidal silicon dioxide (Cabosil) (2%).
  • the meglumine granulation was prepared by a wet-granulation of meglumine (95%) and hydroxypropylcellulose (Klucel) (5%).
  • FIG. 6 graphs percent (%) glipizide released (Y) against time in hours (X). This example demonstrates that different elements of programmed delivery can be combined in a dosage form to obtain release characteristics in a more efficient manner.

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US6261601B1 (en) 1997-09-19 2001-07-17 Ranbaxy Laboratories Limited Orally administered controlled drug delivery system providing temporal and spatial control
US6391336B1 (en) * 1997-09-22 2002-05-21 Royer Biomedical, Inc. Inorganic-polymer complexes for the controlled release of compounds including medicinals
US6448323B1 (en) * 1999-07-09 2002-09-10 Bpsi Holdings, Inc. Film coatings and film coating compositions based on polyvinyl alcohol
US6514533B1 (en) * 1992-06-11 2003-02-04 Alkermas Controlled Therapeutics, Inc. Device for the sustained release of aggregation-stabilized, biologically active agent
US6517868B2 (en) 1999-12-20 2003-02-11 A. Reza Fassihi Amino acid modulated extended release dosage form
US6555139B2 (en) 1999-06-28 2003-04-29 Wockhardt Europe Limited Preparation of micron-size pharmaceutical particles by microfluidization
US6599532B2 (en) * 2000-01-13 2003-07-29 Osmotica Corp. Osmotic device containing alprazolam and an antipsychotic agent
US20040110813A1 (en) * 2002-09-24 2004-06-10 Boehringer Ingelheim International Gmbh Solid telmisartan pharmaceutical formulations
US20050053669A1 (en) * 2003-09-05 2005-03-10 Boehringer Ingelheim International Gmbh Administration form for the oral application of poorly soluble acidic and amphorteric drugs
US20050053653A1 (en) * 2003-09-05 2005-03-10 Argaw Kidane Osmotic delivery of therapeutic compounds by solubility enhancement
US20050142195A1 (en) * 2002-11-21 2005-06-30 Boyong Li Stable pharmaceutical compositions without a stabilizer
US6936275B2 (en) 1999-12-20 2005-08-30 Scolr, Inc. Amino acid modulated extended release dosage form
WO2005124931A1 (en) * 2004-06-08 2005-12-29 Paricon Technologies Corporation Apparatus for applying a mechanically-releasable balanced compressive load to an assembly such as a compliant anisotropic conductive elastomer electrical connector
US20060068010A1 (en) * 2004-09-30 2006-03-30 Stephen Turner Method for improving the bioavailability of orally delivered therapeutics
US20070232785A1 (en) * 2006-03-20 2007-10-04 Franck Weber Process for neutralization of the residual acidity contained in the phenolic compounds
US20080113023A1 (en) * 2005-11-24 2008-05-15 Manabu Nakatani Bilayer tablet comprising telmisartan and diuretic
WO2010042203A1 (en) * 2008-10-10 2010-04-15 Alvine Pharmaceuticals, Inc. Dosage forms that facilitate rapid activation of zymogen
WO2010068789A1 (en) * 2008-12-10 2010-06-17 Transcept Pharmaceuticals, Inc. Polyethylene glycol-coated sodium carbonate as a pharmaceutical excipient and compositions produced from the same
US20100266682A1 (en) * 2008-12-10 2010-10-21 Nipun Davar Polyethylene glycol-coated sodium carbonate as a pharmaceutical excipient and compositions produced from the same
EP2368556A1 (en) 2006-04-27 2011-09-28 Supernus Pharmaceuticals, Inc. An osmotic drug delivery system

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PT1424997E (pt) * 2001-09-14 2008-02-28 Scolr Inc Forma de dosagem de libertação prolongada modulada por aminoácidos
JP2004075582A (ja) * 2002-08-13 2004-03-11 Takeda Chem Ind Ltd 固形医薬組成物に処方される有効成分以外の成分の安定化方法
CN101374497A (zh) * 2006-05-08 2009-02-25 麦克内尔-Ppc股份有限公司 渗透剂型
EP2228066A1 (en) * 2009-03-03 2010-09-15 LEK Pharmaceuticals d.d. Pharmaceutical compositions of sulphonylurea-based active pharmaceutical ingredient with excellent dissolution properties
CN102113961B (zh) * 2011-01-25 2013-11-13 浙江工业大学 一种不对称膜渗透泵胶囊壳的制备方法
JP6691478B2 (ja) * 2013-10-07 2020-04-28 モノソル リミテッド ライアビリティ カンパニー 水溶性遅延放出カプセル、関連する方法および関連する物品

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4111203A (en) * 1976-11-22 1978-09-05 Alza Corporation Osmotic system with means for improving delivery kinetics of system
US4111201A (en) * 1976-11-22 1978-09-05 Alza Corporation Osmotic system for delivering selected beneficial agents having varying degrees of solubility
US4608048A (en) * 1984-12-06 1986-08-26 Alza Corporation Dispensing device with drug delivery patterns
US4755180A (en) * 1986-06-16 1988-07-05 Alza Corporation Dosage form comprising solubility regulating member
US5120548A (en) * 1989-11-07 1992-06-09 Merck & Co., Inc. Swelling modulated polymeric drug delivery device
EP0357369B1 (en) * 1988-08-30 1993-05-12 Pfizer Inc. The use of asymetric membranes in delivery devices
US5225202A (en) * 1991-09-30 1993-07-06 E. R. Squibb & Sons, Inc. Enteric coated pharmaceutical compositions
US5260068A (en) * 1992-05-04 1993-11-09 Anda Sr Pharmaceuticals Inc. Multiparticulate pulsatile drug delivery system

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4111203A (en) * 1976-11-22 1978-09-05 Alza Corporation Osmotic system with means for improving delivery kinetics of system
US4111201A (en) * 1976-11-22 1978-09-05 Alza Corporation Osmotic system for delivering selected beneficial agents having varying degrees of solubility
US4608048A (en) * 1984-12-06 1986-08-26 Alza Corporation Dispensing device with drug delivery patterns
US4755180A (en) * 1986-06-16 1988-07-05 Alza Corporation Dosage form comprising solubility regulating member
EP0357369B1 (en) * 1988-08-30 1993-05-12 Pfizer Inc. The use of asymetric membranes in delivery devices
US5120548A (en) * 1989-11-07 1992-06-09 Merck & Co., Inc. Swelling modulated polymeric drug delivery device
US5225202A (en) * 1991-09-30 1993-07-06 E. R. Squibb & Sons, Inc. Enteric coated pharmaceutical compositions
US5260068A (en) * 1992-05-04 1993-11-09 Anda Sr Pharmaceuticals Inc. Multiparticulate pulsatile drug delivery system

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
G. A. McClelland et al, "The Solubility-Modulated Osmotic Pump: In vitro/In vivo Release of Diltiazem Hydrochloride", Pharma. Research, vol. 8, No. 1, pp. 88-92 (1991).
G. A. McClelland et al, The Solubility Modulated Osmotic Pump: In vitro/In vivo Release of Diltiazem Hydrochloride , Pharma. Research, vol. 8, No. 1, pp. 88 92 (1991). *

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6514533B1 (en) * 1992-06-11 2003-02-04 Alkermas Controlled Therapeutics, Inc. Device for the sustained release of aggregation-stabilized, biologically active agent
US6261601B1 (en) 1997-09-19 2001-07-17 Ranbaxy Laboratories Limited Orally administered controlled drug delivery system providing temporal and spatial control
US6630486B1 (en) 1997-09-22 2003-10-07 Royer Biomedical, Inc. Inorganic-polymer complexes for the controlled release of compounds including medicinals
US6391336B1 (en) * 1997-09-22 2002-05-21 Royer Biomedical, Inc. Inorganic-polymer complexes for the controlled release of compounds including medicinals
US6869976B2 (en) 1997-09-22 2005-03-22 Royer Biomedical, Inc. Inorganic-polymer complexes for the controlled release of compounds including medicinals
US20030170307A1 (en) * 1997-09-22 2003-09-11 Royer Biomedical, Inc. Inorganic-polymer complexes for the controlled release of compounds including medicinals
US6555139B2 (en) 1999-06-28 2003-04-29 Wockhardt Europe Limited Preparation of micron-size pharmaceutical particles by microfluidization
US6448323B1 (en) * 1999-07-09 2002-09-10 Bpsi Holdings, Inc. Film coatings and film coating compositions based on polyvinyl alcohol
US20050238717A1 (en) * 1999-12-20 2005-10-27 Fassihi A R Amino acid modulated extended release dosage form
US6936275B2 (en) 1999-12-20 2005-08-30 Scolr, Inc. Amino acid modulated extended release dosage form
US7229642B2 (en) 1999-12-20 2007-06-12 Scolr, Inc. Amino acid modulated extended release dosage form
US6517868B2 (en) 1999-12-20 2003-02-11 A. Reza Fassihi Amino acid modulated extended release dosage form
US6599532B2 (en) * 2000-01-13 2003-07-29 Osmotica Corp. Osmotic device containing alprazolam and an antipsychotic agent
US8980870B2 (en) 2002-09-24 2015-03-17 Boehringer Ingelheim International Gmbh Solid telmisartan pharmaceutical formulations
US20040110813A1 (en) * 2002-09-24 2004-06-10 Boehringer Ingelheim International Gmbh Solid telmisartan pharmaceutical formulations
US20050142195A1 (en) * 2002-11-21 2005-06-30 Boyong Li Stable pharmaceutical compositions without a stabilizer
US8501227B2 (en) * 2002-11-21 2013-08-06 Andrx Pharmaceuticals, Llc Stable pharmaceutical compositions without a stabilizer
US20050053653A1 (en) * 2003-09-05 2005-03-10 Argaw Kidane Osmotic delivery of therapeutic compounds by solubility enhancement
WO2005023228A1 (en) * 2003-09-05 2005-03-17 Shire Laboratories, Inc. Osmotic delivery of therapeutic compounds by solubility enhancement
US7611728B2 (en) * 2003-09-05 2009-11-03 Supernus Pharmaceuticals, Inc. Osmotic delivery of therapeutic compounds by solubility enhancement
US20050053669A1 (en) * 2003-09-05 2005-03-10 Boehringer Ingelheim International Gmbh Administration form for the oral application of poorly soluble acidic and amphorteric drugs
WO2005124931A1 (en) * 2004-06-08 2005-12-29 Paricon Technologies Corporation Apparatus for applying a mechanically-releasable balanced compressive load to an assembly such as a compliant anisotropic conductive elastomer electrical connector
US20060068010A1 (en) * 2004-09-30 2006-03-30 Stephen Turner Method for improving the bioavailability of orally delivered therapeutics
US20080113023A1 (en) * 2005-11-24 2008-05-15 Manabu Nakatani Bilayer tablet comprising telmisartan and diuretic
US8637078B2 (en) 2005-11-24 2014-01-28 Boehringer Ingelheim International Gmbh Bilayer tablet comprising telmisartan and diuretic
US20070232785A1 (en) * 2006-03-20 2007-10-04 Franck Weber Process for neutralization of the residual acidity contained in the phenolic compounds
EP2368556A1 (en) 2006-04-27 2011-09-28 Supernus Pharmaceuticals, Inc. An osmotic drug delivery system
US20110236369A1 (en) * 2008-10-10 2011-09-29 Bret Berner Dosage Forms That Facilitate Rapid Activation of Zymogen
WO2010042203A1 (en) * 2008-10-10 2010-04-15 Alvine Pharmaceuticals, Inc. Dosage forms that facilitate rapid activation of zymogen
US9017667B2 (en) 2008-10-10 2015-04-28 Alvine Pharmaceuticals, Inc. Dosage forms that facilitate rapid activation of barley protease zymogen
US20100266682A1 (en) * 2008-12-10 2010-10-21 Nipun Davar Polyethylene glycol-coated sodium carbonate as a pharmaceutical excipient and compositions produced from the same
WO2010068789A1 (en) * 2008-12-10 2010-06-17 Transcept Pharmaceuticals, Inc. Polyethylene glycol-coated sodium carbonate as a pharmaceutical excipient and compositions produced from the same

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EP0668755A1 (en) 1995-08-30
NO951996D0 (no) 1995-05-19
TW235239B (sv) 1994-12-01
EP0668755B1 (en) 1998-07-29
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KR950703931A (ko) 1995-11-17
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